The main component of garlic is S-allyl cysteine sulfoxide (alliin), a sulfur-containing amino acid that acts as the precursor for its characteristic odor. This non-volatile derivative of cysteine is stored in the cytoplasm of mesophyll storage cells within the bulb. Conversely, alliinase (C-S lyase), which catalyzes alliin, is localized in the vacuole of the vascular sheath cell of the bulb (3). When garlic tissues undergo disruption during cooking or processing, alliinase acts on alliin to cleave the sulfur-carbon bond. This enzymatic reaction results in the breakdown of alliin into allyl sulfenic acid and aminoacrylic acid. Allyl sulfenic acid is rapidly converted into the odorant allyl thiosulfinate (allicin) via dehydration, producing the distinctive odor of crushed garlic. Allicin, a highly reactive compound, generates various additional odor compounds through reactions with other compounds and self-decomposition (Fig. 1) (4,5). Heating non-crushed garlic inactivates alliinase, preventing allicin formation during cooking and facilitating alliin formation instead (Fig. 2A). Odor compounds generated by allicin (Fig. 2B) include allyl sulfides, allyl methyl sulfides (AMS) and ajoene (Fig. 2C and D). Diallyl disulfide (DADS), a typical allyl sulfide, is formed by non-enzymatic reactions with allyl mercaptan, a degradation product of allicin. Subsequently, DADS is converted to diallyl trisulfide (DATS) and diallyl tetrasulfide, which contain additional sulfur atoms, through autolysis and complex non-enzymatic reactions. These sulfides can be efficiently collected as essential oils by steam distillation of crushed garlic homogenate (Fig. 2C). Garlic produces sulfur-containing compounds during cooking and processing procedures. Ajoene, discovered in 1984, is generated by oil-based heating of crushed garlic and subsequent chemical reactions with three allicin molecules (Fig. 2D) (6). Unlike sulfides, ajoene undergoes minimal production during garlic crushing alone. All of these sulfur-containing compounds are lipophilic and have unique odors. Conversely, aged garlic extract (AGE), obtained by soaking untreated or sliced garlic in a water and alcohol solution for an extended period, contains water-soluble sulfur compounds, including S-allyl cysteine (SAC) and S-allyl mercapto-cysteine (7). In contrast to lipophilic sulfur compounds, these water-soluble compounds lack a strong odor (Fig. 2E).

Garlic consumption is presumed to aid in preventing lifestyle diseases, such as diabetes and atherosclerosis, through various sulfur-containing compounds derived from alliin. The following sections discuss the diverse effects of consuming garlic and its sulfur compounds. The physiological effects of garlic-derived sulfur compounds are summarized in Table I.

Platelet aggregation is a pivotal response in the hemostatic reaction to vascular damage. However, excessive platelet aggregation may indicate a prothrombotic condition. Therefore, suppression of excessive platelet aggregation could reduce the risk of thromboembolic diseases. Garlic intake can significantly inhibit platelet aggregation (8).

SAC-containing AGE reduces platelet adhesion to fibrinogen. This effect reportedly occurs through elevation of the intraplatelet cyclic adenosine monophosphate concentration and inhibition of the bond between the platelet surface adhesion molecule integrin αIIbβ3 and fibrinogen (8).

Various garlic extracts, prepared through diverse methods and conditions, have been tested against human platelets to assess their impacts on platelet aggregation. The results indicated that anti-platelet aggregation activity depends upon the allicin content of the extracts (9). Furthermore, heating of garlic for >10 min before cooking completely suppresses its anti-platelet aggregation activity. There is evidence that light crushing of garlic prior to cooking can preserve its anti-platelet aggregation activity after cooking. These results indicate that the compounds with anti-platelet activity are produced through reactions catalyzed by CS-lyase. Actually, DATS shows potent anti-platelet activity in vitro (10).

To comprehensively assess proteins with post-translational thiol modifications, the shotgun liquid chromatography-tandem mass spectrometry method was applied to Jurkat cells (a human acute T-cell leukemia cell line) that had been treated with allicin (11). The analysis revealed that various proteins, including those associated with the cytoskeleton and glycolysis, undergo oxidative modification by allicin (11). DATS also oxidatively modifies specific cysteine residues of the cytoskeletal protein tubulin (12). DATS exhibits greater reactivity with cysteine residues compared with its saturated structural analogue, dipropyl trisulfide; it also demonstrates potent platelet aggregation inhibitory effects (10). These findings suggest that certain physiological activities of garlic sulfur compounds, including platelet aggregation inhibition, can be attributed to the oxidative modification of cellular proteins (Fig. 3).

Tissue factor (TF) is an important coagulation factor in initiating the extrinsic coagulation pathway. Subendothelial TF is responsible for the initiation of fibrin formation at sites of vascular injury. Tumor necrosis factor-α (TNF-α) induced TF mRNA expression in human umbilical vein endothelial cells was suppressed by the inhibition of JNK signal. Therefore, the inhibition of the JNK pathway by DATS may inhibit the induction of TF by TNF-α. DATS inhibited not only TF activity but also TF mRNA and protein expression in vitro (13). Garlic is a promising food with anti-thrombotic function, which can suppress both primary and secondary clot formation. The anti-thrombotic effect of garlic is beneficial for patients who are allergic or intolerant to aspirin and is expected to be an alternative or complementary therapy to anti-platelet therapy.

A double-blinded placebo-controlled randomized study performed in 51 patients with coronary heart disease (CHD) to examine the effects of time-released garlic powder tablets on the values of 10-year prognostic risk of acute myocardial infarction and sudden death. The 12-month treatment with the garlic resulted in the significant decrease in cardiovascular risk by 1.5-fold in men, and by 1.3-fold in women. Thus, garlic may be crucial for the secondary prevention of atherosclerotic diseases in patients with CHD (14).

Blood pressure-lowering and myocardial protective effects. Hydrogen sulfide (H₂S), a hazardous and toxic gas, is produced in the human body from cysteine via enzymes, including cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). This compound functions as both a neurotransmitter and vasoactive agent, similar to well-known gaseous mediators such as nitric oxide and carbon monoxide (15,16). In addition to endogenously synthesized H₂S, garlic-derived sulfur-containing compounds have been reported to act as H₂S donors, contributing to blood pressure reduction through blood vessel dilation (17). A previous study showed that the addition of garlic extracts to erythrocytes in vitro resulted in H₂S release. Furthermore, application of sulfur-containing compounds from garlic to the aorta and cardiac vessels of rats led to vasodilation. The generation of H₂S by garlic-derived sulfur compounds is attributed to reactions with intracellular glutathione (GSH) and polysulfide compounds (18).

The role of H₂S in the healthy organism is well understood; decreased plasma H₂S concentrations or disturbances in its synthesis in some tissues have been described (19). It has also been reported that vascular diseases are closely related with the downregulation of the H₂S pathway. The decreased plasma H₂S concentrations are observed in patients with hypertension, heart failure or ischemic heart disease in comparison with the normal-control patients (20-23). Moreover, the plasma H₂S in the patients with vascular diseases was correlated with the severity of symptoms; it was significantly lower in acute myocardial infarction and unstable angina in comparison with a stable form of the disease (24). It has also been reported that marked reduction in plasma H₂S in both patients with chronic kidney disease (CKD) and animal CKD models (25-27). Moreover, it was found that low H₂S levels in type 2 diabetes mellitus patients showed a higher risk of cardiovascular disease (28). Thus, the garlic compounds may be contributing the amelioration of pathology of these diseases.

Furthermore, SAC administration increased the blood concentration of H₂S in a rat model of myocardial infarction due to elevated CSE activity in the left ventricle, revealing a myocardial protective effect (29). DATS also protected myocardial cells from high-glucose-induced apoptosis by enhancing CSE-derived H₂S production (30). These findings suggest that garlic can lower blood pressure and protect the myocardium by directly or indirectly increasing the blood concentration of H₂S.

Lipid abnormalities, characterized by elevated levels of triglycerides and cholesterol, high concentrations of low-density lipoprotein (LDL) and low concentrations of high-density lipoprotein (HDL), are recognized as contributors to severe vascular complications including atherosclerosis and myocardial infarction. Consumption of garlic and its sulfur-containing compounds has been reported to improve lipid abnormalities and reduce cardiovascular disease risk by inhibiting LDL oxidation (31,32). AGE administration in apolipoprotein E-deficient mice on a high-fat diet, which serves as an atherosclerosis model, reduced plasma total cholesterol and triglyceride concentrations and suppressed lipid deposition within the vascular lumen, a characteristic of atherosclerotic lesions in the aortic arch (33). Allicin suppresses lipid accumulation, enhances ABC transporter A1 expression in macrophages, and promotes cholesterol efflux from cells by regulating peroxisome proliferator-activated receptor gamma/liver X receptor alpha signaling, which regulates lipid metabolism (34). Additionally, allicin inhibits the expression of the scavenger receptor CD36, responsible for oxidized lipoprotein uptake, and hinders oxidized LDL-induced monocyte differentiation into macrophages (35).

In patients with hyper-homocysteinemia-related coronary artery disease, allicin administration was associated with improved homocysteine levels and reduced carotid artery intima-media thickness (36). Furthermore, individuals with dyslipidemia experienced significant reductions in plasma cholesterol and LDL concentrations, with simultaneous increases in HDL concentrations, after the consumption of garlic powder tablets in the single-blind, placebo-controlled study (37). These findings suggest that garlic and its sulfur-containing compounds can improve lipid metabolism and prevent atherosclerosis by inhibiting macrophage foaming.

Anti-obesity and anti-diabetic effects. In recent years, obesity rates have increased due to altered social eating habits, dietary diversification and lack of exercise (38). Obesity is characterized by excessive body fat accumulation and constitutes a leading cause of metabolic syndrome, which results in lifestyle-related conditions such as diabetes, dyslipidemia and hypertension; it eventually causes severe complications, such as cardiovascular disease (39).

Several studies have indicated that the consumption of garlic and its sulfur-containing compounds may have beneficial effects on obesity and metabolic syndrome. Garlic powder consumption in high-fat diet-induced obese (DIO) mice prevented increases in body weight and adipose tissue mass while improving plasma lipid profiles. Additionally, garlic powder consumption increased the mRNA expression of uncoupling proteins (UCPs) in brown adipose tissue, liver, white adipose tissue (WAT) and muscle. Furthermore, the decrease in mouse body temperature was suppressed, even during exposure to cold temperatures (4˚C) (40). Our previous study revealed that oral administration of garlic oil to DIO rats, obtained through steam distillation of crushed garlic, suppressed weight gain while increasing the UCP expression in brown adipose tissue, thereby enhancing energy expenditure (41). These results indicated that UCPs may be involved in the anti-obesity effects of garlic. Furthermore, the anti-obesity potential of DATS was demonstrated in a rat model. Considering the emerging role of microRNAs (miRNAs) in lifestyle diseases, their roles in the anti-obesity effects of DATS were investigated. Transcriptomic analyses revealed that DATS downregulated miRNA-335 expression and normalized obesity-associated mRNA signatures in the epididymal WAT of obese rats (42).

In a rat model of streptozotocin-induced type 1 diabetes, crushed garlic administration suppressed the elevation of blood glucose, reduced glycated protein levels, increased blood insulin concentrations, and lowered lipid peroxide levels in the pancreas and liver (43). Additionally, raw crushed garlic has been reported to improve the pathological features of metabolic syndrome, including elevated blood glucose levels, impaired glucose tolerance, and fructose-induced dyslipidemia (44,45). Although alliin administration to DIO mice via drinking water did not affect body weight or energy expenditure, it enhanced insulin sensitivity and ameliorated hyperlipidemia (46). Similarly, SAC consumption was associated with enhanced insulin sensitivity (47). These findings suggest that garlic and its sulfur-containing compounds have the potential to ameliorate diabetes-associated pathological conditions, including obesity and glucose intolerance.

AD is a neurodegenerative disorder characterized by progressive memory loss, cognitive impairment and behavioral changes. It accounts for nearly 50% of all dementia cases and is associated with abnormal accumulation of amyloid-β (Aβ) and tau proteins, leading to neuronal damage and neurotransmitter depletion (48). A key pathological feature of AD is a significant reduction in acetylcholine levels due to the excessive activity of acetylcholinesterase (AChE), an enzyme that degrades acetylcholine in the nervous system. Therefore, AChE inhibitors are considered to be promising therapeutic agent for AD.

Several garlic-derived organosulfur compounds have demonstrated neuroprotective effects by targeting multiple pathological pathways of AD. For instance, ajoene and allicin have been reported to inhibit AChE activity, thereby preserving cholinergic function (49,50). Additionally, SAC and DADS exert anti-inflammatory and antioxidant effects by modulating microglial activation and reducing oxidative stress in AD models (51-54). Oral administration of AGE has been shown to suppress Aβ-induced neuroinflammation and improve cognitive function in animal models, suggesting its potential role in preventing AD progression (55).

Recent evidence also indicates that H₂S plays a critical role in neurodegenerative diseases. Studies have reported that plasma H₂S levels are significantly reduced in patients with AD, suggesting an impairment in endogenous H₂S metabolism (56). Similarly, PD, which is characterized by motor system dysfunction due to dopaminergic neuron loss, has been linked to decreased H₂S production in the substantia nigra, likely due to downregulation of CBS (57). Since garlic-derived sulfur compounds can enhance endogenous H₂S production, they may contribute to the amelioration of both AD and PD symptoms. Taken together, these findings highlight the multifaceted neuroprotective potential of garlic-derived sulfur compounds beyond their H₂S-mediated effects. AGE, SAC and DATS have been shown to attenuate oxidative stress, suppress neuroinflammation, and inhibit AChE activity, thereby preserving neuronal function and preventing cognitive decline (58). Given these mechanisms, garlic and its bioactive components hold promise as potential therapeutic agents for neurodegenerative diseases, including AD and PD.

Data from clinical studies suggest that garlic consumption may have effects on cancer prevention. The two main type of compounds that have been shown to have anticancer properties are lipid-soluble allyl sulfur compounds including DADS and DATS, and water-soluble compounds including SAC and S-allyl mercapto-cysteine (59). DATS has demonstrated significant anticancer effects across various cancer types by inhibiting proliferation, inducing apoptosis and autophagy, suppressing invasion and migration, and modulating the tumor microenvironment (60). These multifaceted actions contribute to its potential in both cancer prevention and treatment. Furthermore, DATS has been shown to enhance chemotherapy sensitivity by modulating drug-efflux pump proteins and increasing oxidative stress in resistant cells. Previous studies have identified common chemoresistance-associated genes that impact cancer survival, highlighting the importance of targeting these pathways to overcome resistance (61). Collectively, these findings suggest that DATS could serve as an adjunctive therapy in cancer treatment, particularly in overcoming chemoresistance (62).